Segregating variation in the transcriptome: Cis regulation and additivity of effects

School of Integraive Biology, University of Illinois, Urbana, Illinois 61801, USA.
Genetics (Impact Factor: 5.96). 08/2006; 173(3):1347-55. DOI: 10.1534/genetics.105.051474
Source: PubMed


Properties of genes underlying variation in complex traits are largely unknown, especially for variation that segregates within populations. Here, we evaluate allelic effects, cis and trans regulation, and dominance patterns of transcripts that are genetically variable in a natural population of Drosophila melanogaster. Our results indicate that genetic variation due to the third chromosome causes mainly additive and nearly additive effects on gene expression, that cis and trans effects on gene expression are numerically about equal, and that cis effects account for more genetic variation than do trans effects. We also evaluated patterns of variation in different functional categories and determined that genes involved in metabolic processes are overrepresented among variable transcripts, but those involved in development, transcription regulation, and signal transduction are underrepresented. However, transcripts for proteins known to be involved in protein-protein interactions are proportionally represented among variable transcripts.

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Available from: Elizabeth Ruedi, Feb 27, 2014
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    • "Heritable regulatory variation can broadly be classified as either acting in cis or trans (Skelly et al. 2009). While trans-regulatory effects on gene expression are undoubtedly important, studies in several eukaryotic organisms, including yeast, fruit flies, mice, rats, and humans, suggest that cis-regulatory effects constitute a substantially higher proportion of the genetic variance in gene expression within species than do trans effects (Schadt et al. 2003; Hughes et al. 2006; Petretto et al. 2006; Emilsson et al. 2008; Pickrell et al. 2010; Skelly et al. 2011). In the budding yeast Saccharomyces cerevisiae, for example, nearly 80% of the genes that have transcribed polymorphisms between two diverse strains exhibit allele-specific expression differences (Skelly et al. 2011). "
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    ABSTRACT: Gene expression levels are determined by the balance between rates of mRNA transcription and decay, and genetic variation in either of these processes can result in heritable differences in transcript abundance. Although the genetics of gene expression has been the subject of intense interest, the contribution of heritable variation in mRNA decay rates to gene expression variation has received far less attention. To this end, we developed a novel statistical framework and measured allele-specific differences in mRNA decay rates in a diploid yeast hybrid created by mating two genetically diverse parental strains. We estimate that 31% of genes exhibit allelic differences in mRNA decay rate, of which 350 can be identified at a false discovery rate of 10%. Genes with significant allele-specific differences in mRNA decay rate have higher levels of polymorphism compared to other genes, with all gene regions contributing to allelic differences in mRNA decay rate. Strikingly, we find widespread evidence for compensatory evolution, such that variants influencing transcriptional initiation and decay having opposite effects, suggesting steady-state gene expression levels are subject to pervasive stabilizing selection. Our results demonstrate that heritable differences in mRNA decay rates are widespread, and are an important target for natural selection to maintain or fine-tune steady-state gene expression levels.
    Genome Research 09/2014; 24(12). DOI:10.1101/gr.175802.114 · 14.63 Impact Factor
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    • "The eQTL map information enables genetic regulatory networks to be modeled that can provide a better understanding of the underlying phenotypic variation. It has been successfully applied in humans [38–40], plants [41–44], yeasts [45, 46], worms [47], flies [48], mice [49, 50], pigs [51] and rats [52] populations. These studies showed that transcript abundance was highly heritable and could be linked to either a local locus (cis-eQTL) or a distant locus (trans-eQTL). "
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    ABSTRACT: Background Mapping expression quantitative trait loci (eQTL) of targeted genes represents a powerful and widely adopted approach to identify putative regulatory variants. Linking regulation differences to specific genes might assist in the identification of networks and interactions. The objective of this study is to identify eQTL underlying expression of four gene families encoding isoflavone synthetic enzymes involved in the phenylpropanoid pathway, which are phenylalanine ammonia-lyase (PAL; EC, chalcone synthase (CHS; EC, 2-hydroxyisoflavanone synthase (IFS; EC1.14.13.136) and flavanone 3-hydroxylase (F3H; EC A population of 130 recombinant inbred lines (F5:11), derived from a cross between soybean cultivar ‘Zhongdou 27’ (high isoflavone) and ‘Jiunong 20’ (low isoflavone), and a total of 194 simple sequence repeat (SSR) markers were used in this study. Overlapped loci of eQTLs and phenotypic QTLs (pQTLs) were analyzed to identify the potential candidate genes underlying the accumulation of isoflavone in soybean seed. Results Thirty three eQTLs (thirteen cis-eQTLs and twenty trans-eQTLs) underlying the transcript abundance of the four gene families were identified on fifteen chromosomes. The eQTLs between Satt278-Sat_134, Sat_134-Sct_010 and Satt149-Sat_234 underlie the expression of both IFS and CHS genes. Five eQTL intervals were overlapped with pQTLs. A total of eleven candidate genes within the overlapped eQTL and pQTL were identified. Conclusions These results will be useful for the development of marker-assisted selection to breed soybean cultivars with high or low isoflavone contents and for map-based cloning of new isoflavone related genes.
    BMC Genomics 08/2014; 15(1):680. DOI:10.1186/1471-2164-15-680 · 3.99 Impact Factor
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    • "There are greater contributions of cis than trans variants to interspecific divergence in expression regulation (Wittkopp et al. 2004; Lemos et al. 2008; Graze et al. 2009; Tirosh et al. 2009; Emerson et al. 2010; McManus et al. 2010). However, the story within species is less clear: although there is abundant regulatory variation (Townsend et al. 2003; Morley et al. 2004; Wayne et al. 2004), there are contradictory findings on the relative importance of cis versus trans variation (Brem et al. 2002; Schadt et al. 2003; Hughes et al. 2006; Genissel et al. 2008; Lemos et al. 2008; Wang et al. 2008; Wittkopp et al. 2008b). The lack of consensus may reflect differences between experimental designs: studies that use expression QTL (eQTL) designs or multiple chromosome substitutions have found many more transacting variants than cis-acting variants (Brem et al. 2002; Schadt et al. 2003; Genissel et al. 2008; Wang et al. 2008). "
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    ABSTRACT: The mechanistic basis of regulatory variation and the prevailing evolutionary forces shaping that variation are known to differ between sexes and between chromosomes. Regulatory variation of gene expression can be due to functional changes within a gene itself (cis), or in other genes elsewhere in the genome (trans). The evolutionary properties of cis mutations are expected to differ from mutations affecting gene expression in trans. We analyze allele-specific expression across a set of X substitution lines in intact adult Drosophila simulans to evaluate whether regulatory variation differs for cis and trans, for males and females, and for X-linked and autosomal genes. Regulatory variation is common (56% of genes), and patterns of variation within D. simulans are consistent with previous observations in Drosophila that there is more cis than trans variation within species (47% vs. 25%, respectively). The relationship between sex-bias and sex-limited variation is remarkably consistent across sexes. However, there are differences between cis and trans effects: cis variants show evidence of purifying selection in the sex towards which expression is biased, while trans variants do not. For female-biased genes, the X is depleted for trans variation in a manner consistent with a female-dominated selection regime on the X. Surprisingly, there is no evidence for depletion of trans variation for male-biased genes on the X. This is evidence for regulatory feminization of the X, trans acting factors controlling male-biased genes are more likely to be found on the autosomes than those controlling female-biased genes.
    Genome Biology and Evolution 04/2014; 6(4). DOI:10.1093/gbe/evu060 · 4.23 Impact Factor
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